This proposal focuses on the biological functions of the VHL tumor suppressor (pVHL), and how pVHL inactivation leads to renal cell carcinoma (RCC). The long-term goals of this research are to elucidate mechanisms of renal tumorigenesis and metastasis and to apply these findings to the development of effective therapeutic approaches to disease management. Inactivation of the VHL gene is central to the initiation of clear cell RCC. pVHL functions in a complex with Elongins B and C and cul-2. In this complex, pVHL is involved in cell cycle control as well as regulation of mRNA expression. The met receptor tyrosine kinase is implicate in development of papillary RCC. Met is the receptor of HGF/SF, a pleiotropic growth factor that acts on a number of cell types, mainly epithelial. Met is expressed and is functional in cell lines derived from clear cell tumors. Our observations indicate that pVHL may be important in cell-cell signaling and may control cellular interactions with its environment tumors. Our observations indicate that pVHL may be important in cell-cell signaling may control cellular interactions with its environment, including both the elaboration of growth factors and responsiveness to growth factors in renal epithelial cells. We hypothesize that pVHL may control expression of components that are involved in growth control and in cellular invasion. In addition, we postulate that pVHL inactivation and a loss of these controls leads to a more invasive phenotype, and the responsiveness of pVHL-negative RCC to extracellular signals such as HGF/SF contributes to tumor initiation and progression in patients with clear cell RCC. The specific aims of our studies will be (1) to determine pVHL structure-function relationships in control of HGF/SF responsiveness in RCC cell lines; (2) to determine whether constitutive met activation in RCC cell lines results in enhanced invasiveness and/or tumorigenicity; (3) to determine the mechanisms of pVHL regulation of matrix metalloproteinases and their inhibitors of RCC cells; and (4) to determine whether pVHL controls intracellular met signaling through the STAT signal transduction pathway in RCC cells. From these studies, we will gain new insights into the molecular mechanisms of pVHL tumor suppressor, as well as the genetic factors that contribute to initiation and progression of renal cancers.